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A. Chiaravalloti et al.
g
i
h
j
Fig. 8.5 (continued)
8 Amyloid Imaging
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145
a
b
de
c
Fig. 8.6 Axial 18F-FDG PET scan in (a) in a subject with
clinical suspect of frontotemporal dementia. In (b), we
report the axial MR images showing a signicant cortical
atrophy involving in particular the left temporal lobe
(arrow); in (c),
18
F-FDG PET/MR fusion imaging showing a signicant reduction of brain glucose consumption
in the left frontal lobe and a mild decrease in glucose con-
Fig. 8.7 A 66-year-old male patient was examined for
clinical suspicion of Alzheimer’s disease with
18
F-utemetamol PET/CT scans. Both scans con-
and
rmed diagnosis. In the left panel, axial
18
F-FDG
18
F-FDG PET
views in different color scales show decit of glucose
sumption in the left temporal lobe. In (d), we report an
axial image of
18
F-orbetaben PET scan showing no signicant amyloid burden in brain. Nevertheless, due to the
presence of cortical atrophy, interpretation of PET scan is
doubtful in the temporal lobe (arrow).
18
F-Florbetaben
PET/MR fusion imaging in (e) shows no signicant amyloid burden in the left temporal lobe
metabolism in left parietal and temporal regions. In the
right panel axial
18
F-utemetamol PET views in different
color scales show pathological amyloid burden in frontal
and parietal regions bilaterally and in left temporal lobe
146
ac
bd
bc
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Fig. 8.8 A 62-year-old
male patient was
examined for clinical
suspicion of
frontotemporal dementia
18
F-FDG and
with
18
F-utemetamol PET/
CT scans. Axial
18
F-FDG PET views (a,
b) show decit of
glucose metabolism in
left frontal and temporal
lobes, conrming
clinical diagnosis.
Corresponding axial
18
F-utemetamol PET
views (c, d) show no
signicant amyloid
burden in the same
regions
A. Chiaravalloti et al.
a
Fig. 8.9 Delayed acquisition (120 min) in a 72-year-old
woman showing a poor count in brain PET acquisition
due to a signicant washout of the radiolabeled compound
18
F-orbetaben). PET maximum intensity projection is
(
shown in (a), while PET and PET/CT images are shown in
(b) and (c)
8 Amyloid Imaging
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147
8.6 PET/CT Acquisition Protocols
PET/CT imaging is usually performed 90–110min
after the injection of ~300 MBq of the radiolabeled compound (35, 38, 39, 42) with a PET
acquisition time of 20min [20]. Since movement
artifacts may occur during the duration of the
scan, especially in less compliant patients, due to
the advanced disease, a study has been carried out
in order to investigate the inuence of scan duration on the evaluation of PET images with
18
F-orbetaben: the authors concluded that the
agreement among readers of the scans lasting 20,
10, and 5 min, respectively, was good and, in particular, there were not differences in the identication of healthy controls from patients [21].
8.7 Variants andPitfalls
Due to the rapid brain washout of the tracer, it is
not uncommon, in late scans following more than
2 h the tracer administration, to obtain lowquality PET images, with a poor count (Fig.8.9).
As already reported, the ideal standard imaging
should be performed 90 min following the
injection.
No signicant diagnostic pitfalls are reported
in literature, linked to the distribution of the tracers, with the exception of a certain quote of nonspecic uptake in the skull and in the white
matter [22] and the possibility to detect tracer
uptake in cardiac amyloidosis. Cardiac amyloidosis is an under-recognized cause of left ven-
abc
def
Fig. 8.10 Axial 18F-orbetaben PET (a), CT (b), and
fused PET/CT (c) images showing no tracer uptake in a
cortical–subcortical area of previous stroke in the right
parietal lobe (arrow) in a 70-year-old male subject. In the
same subject, another stroke was detectable in the left
temporal and parietal lobe (d–f) with no signicant uptake
of the radiolabeled compound (f, arrow)
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abc
def
A. Chiaravalloti et al.
Fig. 8.11 In a patient with Alzheimer’s disease, examined with 18F-orbetaben PET/CT, an example of motion artifacts
due to the head rotation between PET (a, d) and CT (b, e) scans, with abnormal PET/CT fusion imaging (c, f, arrows)
tricular hypertrophy and heart failure in the
elderly; to date, molecular tracers assessing amyloid plaque burden and sympathetic innervation
may be useful for the noninvasive evaluation
diagnosis and risk stratication of patients with
suspected cardiac amyloidosis [
23]. Recently, a
pilot study demonstrated constant cardiac uptake
with 18F-orbetapir in 15 patients with cardiac
amyloidosis [24]. However, studies on larger
population are required to establish the role of
this tracer in screening patients with amyloidosis
for cardiac involvement and in disease
monitoring.
In our experience, we documented absent
uptake in postischemic lacunar areas (Fig.8.10).
Conversely, technical artifacts are common to
“traditional” PET/CT imaging with 18F-FDG.For
the clinical conditions of examined patients in
peculiar clinical settings, the most common artifact can be linked to patient movement of the
head and neck occurring between PET and CT
imaging (Fig.8.11).
Finally, in patients with negative amyloid
tracer PET/CT scan another cause of dementia
should be considered. As for vascular dementia,
CT component of the exam can lead to few but
meaningful information on patient’s brain, as in
the condition of idiopathic normal pressure
hydrocephalus (Fig.8.12). In this clinical condition, it has already reported the utility of CT,
while 18F-FDG PET may be associated with preserved cortical metabolism [25]. Similar ndings
seem to be documented with amyloid PET tracers [26]. In particular, 18F-orbetaben PET/CT
8 Amyloid Imaging
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a a’ b b’ c
d d’ e e’ f
149
Fig. 8.12 A 59-year-old female patient was examined by
18
F-FDG and 18F-utemetamol PET/CT scans for clinical
dementia. Axial
(a′) views show no signicant amyloid burden, while
18
F-FDG PET (b) and PET/CT (b′) do not show de-
axial
18
F-utemetamol PET (a) and PET/CT
cit of glucose metabolism. In corresponding axial CT
can help determine which idiopathic normal
pressure hydrocephalus patients will benet from
shunt surgery by discriminating concomitant AD,
as reported in a recent study [27].
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PET Myocardial Perfusion Imaging:
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82
Rb
MariaLuisaDe Rimini andGiovanniBorrelli
9
9.1 PET Myocardial Perfusion
Tracers: Introduction
The most common PET tracers for myocardial
perfusion imaging (MPI) and for quantication
of myocardial blood ow (MBF) are 13N-labeled
ammonia (13NH3), 15O-labeled water (15O-H2O),
and 82Rb [1], they are reported in Table9.1 showing their main features where, obviously, the
common feature for each of them is the decay.
Positron rapidly loses kinetic energy before
colliding with an electron. Both particles annihilate and emit 2 gamma rays with energies of 511
keV in opposite directions. Thus, if in a PET
scanner the ring of detectors surrounding the
patient detects a coincidence pair of 511 keV
gamma rays, it is registered as an event. When
many similar events are detected, the activity distribution of the positron-emitting radionuclide
may be constructed within the volume of the left
ventricle (LV) and cardiac imaging will be
obtained.
Reliable attenuation correction (AC) methods
for PET require determination of an attenuation
map, which represents the spatial distribution of
linear attenuation coefcients at 511
keV. Actually PET/CT scanners allow AC for
PET images and morpho-functional correlations.
M. L. De Rimini (*) · G. Borrelli
Nuclear Medicine—PET UNIT, Health Service
Department, AO Ospedali dei Colli, Naples, Italy
marialuisa.derimini@ospedalideicolli.it
e-mail:
PET MPI is increasingly being used for noninvasive detection of coronary artery disease
(CAD), despite its use can be limited by the
shortcomings of the current perfusion tracers due
to the need of in-house such as 15O-H2O, or
onsite/nearby for 13N-NH3, cyclotron and by
commitment to costly generators (82Rb).
Owing to the short half-lives of tracers
(Table 9.1), their use with treadmill exercise
stress test is not possible (82Rb and 15O-H2O) and
no/or not practical (13N-NH3).
In the recent years, the development of a
18
F-labeled PET perfusion tracer has gathered
considerable interest. The longer half-life of 18F
(109 min) would make the tracer available as a
unit dose from regional cyclotrons and allows the
use of PET associated with treadmill exercise
testing. Furthermore, the short positron range of
18
F would result in better image resolution.
18
F-Flurpiridaz is by far the most thoroughly
studied in animal models and is the only 18F-based
PET MPI radiotracer currently undergoing clinical evaluation. Preclinical and clinical experience
with 18F Flurpiridaz demonstrated a high myocardial extraction fraction, high resolution of images
and defects, high myocardial uptake, slow myocardial clearance, and high myocardial-tobackground contrast stable over time. On this
basis, 18F-labeled myocardial perfusion tracers
could be an ideal PET MPI radiotracer and preclinical data are encouraging [2].
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024
F. Calabria, O. Schillaci (eds.), Radiopharmaceuticals,
https://doi.org/10.1007/978-3-031-54196-4_9
151
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M. L. De Rimini and G. Borrelli
Table 9.1
PET tracer
13
H
82
a
The use of 3D PET scanners and software allowing to inject half activity of 82Rb with a preserved image quality, the
calculated effective dose has been estimated 1.26 mSv for rest and stress scans
has prognostic value in patients affected with
CAD, allowing relevant additional advantages
such as MBF estimation.
between tracer’s kinetics and MBF. Differences
Cardiac PET tracers
Physical
half-life (min) Extraction Production
NH3 9.96 80% Onsite/nearby
15
O 2.05 Diffusible On-site cyclotron 1.1 700–1500 0.7–1.4
2
Rb 1.16 50–60% Generator 2.6 1100–1500 1.8–3.5
cyclotron
PET MPI provides for accurate diagnosis and
Mean positron
range Dose (MBq)
0.7 370–740 0.7–1.5
15
O-H2O PET attractive is due to - Ability
The
Effective dose
(mSv)
1.26
a
to accurately quantify MBF based on high extraction fraction and the short physical half-life making it possible to perform a short stress and rest
It should be underlined the close correlation
data acquisition protocol with a lowering radiation exposure [4].
in the rst-pass extraction of PET MPI tracers
inuence their myocardial uptake relating to
Note
regional blood ow and, at the same time, a better
rst-pass extraction of tracers inuences a more
effective evaluation of MBF [1].
• 15O-H2O is not typically used for the assess-
ment of myocardial perfusion alone, but it is
the ideal ow tracer, including 100% extrac-
Note
tion from blood to tissue, and 100% retention
(no washout) allowing a linear relationship
• Resting MBF, measured with these tracers in
healthy human, is approximately 1.0 mL/
(min·g) which increases threefold or higher
than 3.0 mL/(min g) under pharmacological
stressor/vasodilator: adenosine, dipyridamole,
or regadenoson [3]. The techniques for noninvasive ow estimates with compartmental
modeling can accurately reect regional MBF
up to 5.0 mL/(min g).
between MBF and the measured tracer activity over a wide range of ow rates.
• Currently, 13N-NH3 and 82Rb are the two more
commonly used tracers in routine clinical
environment, with a small number of centers
worldwide using 15O-H2O.Nevertheless they
have limited (<100%) extraction and retention, do not exhibit such a linear property
between MBF, tracer uptake, and retention
rates, indeed roll-off of tracer uptake in the
myocardium can underestimate the assess-
9.1.1 Labeled Water (15O-H2O)
ment of regional MBF at high ow.
It is metabolically inert and freely diffusible
through capillaries and cell membranes, with
high extraction fraction. This feature allows
appropriate quantication of MBF, taking advantage of the optimal tracer kinetic going in and out
of the compartment in study, without undergoing
any change by the system itself. Conversely, the
same feature prevents the uptake in the myocardium, making complex and extremely limited the
realization of diagnostic MPI.
9.1.2 13N Ammonia (13N-NH3)
It is characterized by rapid blood disappearance.
In the arterial blood, it coexists in the neutral
form (NH3) in balance with its charged ion
(NH4). 13NH3 diffuses rapidly through the
plasma and cell membranes, allowing full extraction from the vascular pool and the rapid trapping
within the myocytes.
9 PET Myocardial Perfusion Imaging: 82Rb
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153
Myocardial retention of 13N-ammonia may be
heterogeneous, even in normal subjects, considering that tracer retention in the lateral wall of the
LV is about 10% less than that of other segments
and the mechanism of this nding is unknown.
13
N-NH3 images also may be degraded by occasional intense liver activity, which can interfere
with the evaluation of the inferior wall.
As with other nondiffusible tracers, the tissue
extraction decreases with the increase in MBF, in
linear relation for the ow values up to 2.5 mL/
min/g. So, if in the healthy heart the fraction of
the myocardial extraction of 13N-NH3 at the rst
passage is 0.83 for ow = 1 mL/min/g, it drops to
0.60 for ow = 3 mL/min/g. The ow and perfusion studies (for activity i.v. 370 MBq) are of
good quality, with the exception of conditions
including patients affected with dysfunctionally
LV or chronic lung diseases and occasionally in
smokers. Although the sequestration of
13
N-ammonia in the lungs is usually minimal, in
these selected population of patients it may be
necessary to prolong the time between injection
and scan for optimizing the myocardium/background ratio [1, 5].
In the assessment of LV contractile function
with PET-gated scan, 13N-NH3 and 82Rb provide
good quality imaging; however, for evaluating
LV function really at peak of stressor test, 82Rb is
the preferred one because of the following 13NNH3 kinetic properties:
Waiting time between injection and scan: 3–4
min; time for both rest and pharmacological
stressor acquisitions:
82
Rb: 35–45min.
13
N-NH3 about 120 min;
9.2 Rubidium-82
82
Rb is a positron emitter tracer used in PET for
MPI and MBF studies. It is a monovalent cationic
analog of potassium, shows kinetic properties
similar to those of Thallium-201, indeed the 82Rb
myocardial uptake is conditioned by the coronary
ow and requires active transport via the sodiumpotassium exchange mechanisms [4, 5].
The short physical half-life of 82Rb and the
advantage of production via a generator with
rapid reconstitution allow fast sequential perfusion imaging and high patient throughput.
82
After i.v. injection,
Rb rapidly crosses the
capillary membrane, myocardial uptake is dependent on coronary blood ow and requires active
transport via the sodium/potassium adenosine triphosphate transporter. 82Rb extraction can be
altered by severe acidosis, hypoxia, and ischemia, conrming that 82Rb uptake is both a function of blood ow and myocardial cell integrity
[5]. The single-capillary transit extraction fraction of 82Rb exceeds 50%. As 13N-NH3 and other
nondiffusible tracers, 82Rb net extraction fraction
decreases in a nonlinear fashion with increasing
MBF.Between the two 82Rb has a substantially
lower extraction fraction (about 35% at peak
stress) and tracer retention than does
13
N-ammonia; however, quantication of MBF
with 82Rb was validated against H
15
O and was
2
found to be accurate at high ow rates.
9.2.1 Production andKinetic
82
Rb is produced by nuclear decay of Strontium-82
(82Sr) via a commercially available generator,
obviating the need for a cyclotron and allowing
the advantage of PET cardiac studies even in
those structures without a cyclotron. 82Rb generator can only be used with the calibrated
CARDIOGEN-82® infusion system (Fig. 9.1a).
The infusion system ensures accurate dosing
with minimal operator interface and minimizes
the radiation exposure.
The system contains shielding vault for
CardioGen-82® Generator and waste container.
82
Sr/82Rb generator for producing 82Rb chloride (82RbCl) for intravenous administration use
has been provided with initial U.S.FDA Approval
in 1989. Cardiogen can be imported in Italy,
thanks to the Decree 1997, 11 February.
The 82Rb parent radionuclide is 82Sr that can
only be produced efciently with a high-energy
cyclotron (~70 MeV) by proton spallation of
molybdenum with a high-energy (800 MeV)
accelerator, followed by chemical purication.
The 82Sr decays to 82Rb by electron capture, it has
a half-life of 25.5 days, which allows the clinical
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